The goal of this project is to determine the relationship between the ionic and electrical changes which occur at the borders of the ischemic zone. Our hypothesis is that unique combinations of [K+]e and pH changes which occur at the ischemic borders during the first 10 minutes of acute no-flow ischemia result in electrophysiological changes that lead to the creation of reentry circuits and the initiation of ventricular fibrillation. We have three specific aims: 1. To correlate the ionic events which occur at the ischemic borders with the simultaneously occurring changes in conduction and refractoriness. 2. To determine as precisely as possible, the causes of the changes in conduction and refractoriness which occur at the borders and in the center of the ischemic zone. 3. To determine the effects of ischemic pre-conditioning on the ionic and electrophysiologic changes. We will employ the in-situ porcine heart and the isolated perfused rabbit papillary muscle. In the porcine hearts we will determine whether regions with increased extracellular potassium, but only minimally depressed pHe, are regions of very slow conduction and whether regions of very slow conduction are regions of high extracellular potassium but only minimally depressed pHe. We will test the hypothesis that premature beats introduced in close proximity to such regions cause reentry and lead to ventricular fibrillation. We will also determine whether there is a fundamental difference in the effect of ischemic re-conditioning on the ionic and electrical changes which occur in the center and at the borders of the ischemic zone. In the isolated perfused papillary muscle, we will determine the role of factors other than the rise in extracellular potassium on the changes in resting membrane potential, of factors other than the change in resting membrane potential on the decrease in Vmax of the action potential upstroke, and of factors other than the increase of Vmax of the action potential upstroke on the changes in conduction, under conditions which model the center and the border of the ischemic zone. We will employ agents known to alter the intracellular changes in sodium, calcium and pH associated with acute ischemia in order to determine the contribution of these intracellular ionic changes to the electrophysiologic changes. In both the in-situ porcine heart and the perfused papillary muscle preparations we will determine the relationship between action potential duration and refractoriness and the inhomogeneity of the recovery of excitability at the center and the margin of the ischemic zone. The data from these studies will allow us to understand more completely the factors that render the borders of the ischemic zone critically important in the pathogenesis of ventricular fibrillation and sudden cardiac death during the early phase of acute myocardial ischemia and to develop strategies aimed at eliminating this catastrophic outcome.